Amyloid fibrils formed from misfolded proteins or peptides are a hallmark of many neuronal diseases, such as, for example, Alzheimer's disease. (Soto, C. Nature Rev. Neurosci. 2003, 4: 49; Agorogiannis, E. I., et al., Neuro path. Appl. Neurobiol. 2004, 30:215; Kelly, J. W. Structure 1997, 5:595.) Amyloid fibrils have also been associated with other, non-neuronal diseases and conditions, such as, for example, those listed in Table 1.
Amyloid fibrils and plaques are rich in beta sheet structure. A-beta is a peptide found in amyloid fibrils and plaques. Researchers have associated the development of Alzheimer's disease (AD), with the interaction of A-beta peptides, oligomers, and fibrils with cellular components in the brain. (Dawbarn, D., and Allen, S. J. Neurobiology of Alzheimer's disease, second ed., Oxford University Press, Oxford, 2001; Pereira, C., et al., J. Mol. Neurosci. 2004, 23: 97.) The interaction between cellular proteins, such as, for example, catalase, ABAD (beta amyloid-binding alcohol dehydrogenase) and RAGE (receptor for advanced glycation end products) and aggregated A-beta-amyloid fibrils (A-beta fibrils), for example, have been reported for their potential contribution to A-beta-induced neurotoxicity in the pathogenesis of AD. (Milton, N. G. N. Biochem. J. 1999, 344: 293-296; Milton, N. G. N., et al. Neuroreport 2001, 121: 2561; Yan, S. D., et al. Nature 1997, 389: 689; Yan, S. D., et al. J. Biol. Chem. 1999, 274: 2145; Lustbader, J. W., et al. Science 2004, 304: 448; Yan, S. D., et al. Nature 1996, 382: 685; Yan, S. D, et al., Am. J. Pathol. 1999, 155: 1403; Yan, S. D., et al., Biochim. Biophys. Acta 2000, 1502: 145; K. Takuma, J. Yao, J. Huang, H. Xu, X. Chen, J. Luddy, A.-C. Trillat, D. M. Stern, O. Arancio, S. S. Yan, FASEB J. 2005, 19(6), 597-598; Takuma, K., et al., FASEB J. 2005, 19(6): 597-598)
Several classes of small molecule therapeutics are used clinically to treat the symptoms of AD, such as, for example, inhibitors of cholinesterase. (Francis, P. T., et al., Trends Pharm. Sci. 2005, 26: 104; Conway, K. A., et al., Curr. Pharm. Design 2003, 9: 427.) Current strategies to modify directly the pathology of AD using synthetic molecules are focused mainly on slowing down the production of A-beta peptide or preventing the growth of A-beta fibrils. (C. Schmuck, et al., ChemBioChem 2005, 6: 1; C. N. Johnson, et al., Drug Dis. Today 2004, 1: 13; M. S. Parihar and T. Hemnani, J. Clin. Neurosci. 2004, 11: 456; V. M.-Y. Lee, Neurobio. Aging 2002, 23: 1039; B. Bohrmann, et al., J. Biol. Chem. 1999, 274: 15990; F. G. De Felice, et al., FASEB J. 2004, 18:1366; M. A. Findeis, Biochim. Biophys. Acta 2000, 1502:76; J. E. Gestwicki, et al., Science 2004, 306: 865).
Other strategies focus on disrupting the fibrils so that they disassemble into their A-beta peptide components. These approaches may increase the amount of A-beta peptide, A-beta-dimers, or small A-beta oligomers in neurons, which may have a toxic affect.
Thioflavin T (ThT) a fluorescent molecule (FIG. 1b)—is used extensively for the characterization of A-beta fibrils (LeVine III, H. Meth. Enzym. 1999, 309: 274) and for the detection of aggregation of A-beta in solution. (Blanchard, B. J., et al., Proc. Nat. Acad. Sci. USA 2004, 101: 14326; Ono, K., et al., J. Neurochem. 2002, 81: 434.) Several groups have studied the interaction of ThT with A-beta fibrils by fluorescence and showed that ThT binds uniformly to the bulk of A-beta fibrils with high affinity (Kd's ranging from high nM to low μM). (LeVine III, H. Protein Sci. 1993, 2: 404; LeVine III, H. Amyloid 1995, 2: 1; LeVine III, H. Arch. Biochem. Biophys. 1997, 342: 306; Lockhart, A., et al., J. Biol. Chem. 2005, 280: 7677; Krebs, M. R. H., et al., J. Struct. Biol. 2005, 149: 30). Thioflavin derivatives have been reported to be used in the diagnosis of Alzheimer's and in in vivo imaging, and Congo Red (CR) is used by researchers to stain amyloid plaques found in patients with Alzheimer's disease. (Klunk, W., et al., U.S. Patent Application Publication No. 20050043377 (2005); C. A. Mathis, et al., Current Pharm. Design, 2004, 10:1469-92; and Hintersteiner, M., et al., Nature Biotechnology, 2005, 23:577-83.)
Molecular coatings on metallic and polymeric surfaces are used frequently to attenuate interactions of proteins with artificial materials for biological studies and biotechnology applications. (Chapman, R. G., et al., J. Am. Chem. Soc. 2000, 122: 8303; Mrksich, M., et al., Proc. Nat. Acad. Sci. USA 1996, 93:10775; Chiu, D. T., et al., Proc. Nat. Acad. Sci. USA 2000, 97: 2408; Chen, X., et al., Langmuir 2002, 18: 7009; Siegers, C., et al., Chem. Eur. J. 2004, 10: 2831.)
There is a need for novel methods and compounds for diagnosing and treating amyloid-associated diseases, for example, neuronal diseases and conditions, with a smaller incidence of toxicity.